Ablating Satb1 reprograms the differentiation trajectory of exhausted CD8+ T subsets to enhance antitumor immunity.

INTRODUCTION

Under chronic infections or in tumors, persistent antigen exposure drives CD8+ T cell exhaustion, a heterogeneous state encompassing a differentiation continuum from stem-like progenitor (Tpex) cells through transitory effector-like (Tex-int) cells to terminally exhausted (Tex-term) subsets. Among these T cell subsets, Tex-int cells serve as the primary population responsible for direct tumor cell killing. However, the intrinsic regulatory mechanisms that govern the Tpex-to-Tex-int transition remain incompletely defined.

METHODS

In this study, we explore the role of special AT-rich sequence-binding protein 1 (SATB1) in the differentiation of Tex-int cells from their precursors. We observed downregulation of SATB1 during Tpex-to-Tex-int differentiation in tumors. Notably, the genetic ablation of Satb1 in T cells markedly expanded the population of tumor-infiltrating CD8+ T cells (CD8+ TILs).

RESULTS

Ablating Satb1 not only promoted the differentiation of Tex-int cells from Tpex cells within the tumor microenvironment but also remodeled T cell differentiation in tumor-draining lymph nodes (TdLNs) by expanding the Tpex pool from tumor-specific memory CD8+ T cells (TTSM) and driving the Tpex1 to Tpex2 transition, thereby augmenting Tex-int production in tumors. Although early-stage Tex-int cells in Satb1-deficient mice displayed transient functional impairment relative to controls, this difference was no longer evident in late-stage tumors, where sustained Tex-int accumulation correlated with significantly suppressed tumor growth and prolonged survival.

DISCUSSION: Our results identify SATB1 as a pivotal regulator of exhausted CD8+ T cell subset differentiation and suggest its targeting as a promising strategy to expand the Tex-int population for enhanced cancer immunotherapy.